The long-term goals of this study are to assess safe methods for inducing remission (Honeymoon period) and prolonging the duration of remissions in newly diagnosed type 1 (insulin- dependent) diabetes. Because of the current widespread research use of immunosuppressant drugs for remission induction, less toxic methods would be advantageous. In our clinic using a randomized pilot study, intensive metabolic control was as effective as reports using more toxic treatments. Thus, the specific aims of this application are to evaluate intensive metabolic control using 2 methods and compare these results to natural (spontaneous) remission rates using a randomized controlled and long-term follow-up experimental design. To improve our knowledge of the mechanisms involved in the cause of remission induction, a variety of immune and metabolic studies are performed. This information will provide data that will permit a more rational approach to the safe and effective treatment of new diabetic patients. Metabolic studies are designed to examine islet B cell secretory reserve by measuring basal and stimulated circulating C-peptide levels and insulin resistance is measured by the euglycemic insulin clamp technique. Thus, both sides of insulin function (secretion and action) are examined to understand why blood glucose levels are normal in remission. This design of in vivo metabolic phenomena is used since C-peptide levels only increase slightly during remission and no measurements of insulin action or resistance are reported in the remission phase of diabetes. To better understand how the immune system is related to the remission phase, a variety of novel and unique immune tests are performed, all of which correlate to new onset type 1 diabetes. These tests include immune islet killing, natural killer cell activity and antibody mediated islet killing. Additionally, complement activation and its relation to the immune cause of remissions is evaluated by assessing circulating levels of C5a, C4a, C3a and factor B. complement is a system comprised of over 20 proteins that can kill cells e.g., islets and this system has been shown by us to be activated in new onset patients. Since factor B appears important in islet killing and is associated with islets and reactive to islet cell antibody, factor B islet synthesis and cellular location will be determined. The results of this study could change the direction of current thoughts and practices regarding remission induction and the treatment of new onset type 1 diabetes.